Mechanisms in Chronic Kidney Disease and Associated Cardiovascular Remodeling Contributes to the Progression of Cognitive Impairment in Women

Abstract

IntroductionIn end‐stage chronic kidney disease (CKD) (stages 4‐5) the prevalence of cognitive impairment (CI) has been estimated at 30‐60%, twice the values observed in age‐ and sex‐matched controls. CKD is greater in females vs. males due to a higher risk of renal infections, especially during the pregnancy, which may result in the renal complications later in life, when the level of protective estrogen declines. Cardiovascular diseases (CVD) including hypertension and increased central arterial stiffness (CAS) accompany CKD development across all stages of this disease. CAS drives pulse pressure (PP) and pulsatile component index (PCI) increases and cerebral microvascular damage resulting in a reduction of blood supply to the brain hereby contributing to CI. Elevated PP and PCI are associated with higher mortality in CVD and CKD independently of BP. Moreover, PP is a cardiovascular risk factor independent on PCI in women >55 years.HypothesisThe aim of the study was to determine whether CKD potentiates development of CI due to cardiovascular remodeling and whether CI in CKD is more pronounced in women. Furthermore, this study also aimed to determine whether reduced estrogen levels in older women with CKD contribute to the progression of CI.MethodsAll research was performed in accordance with the guidelines and regulations set forth by the Declaration of Helsinki regarding the use and enrollment of human subjects in research. A total of 26 female CKD patients (age 45‐50 years and older, CKD stage 4, GFR 15‐29, and Creatinine > 1mg/dL) and 30 age and sex‐ matched healthy control patients were enrolled with exclusion criteria (history of HIV, hepatitis, malignancies, admission and/or surgery for trauma, head injury and pregnancy at time of enrollment). Blood pressure (systolic and diastolic blood pressure (SBP, DBP) was measured, clinical blood work, echocardiography (ECHO) and mini‐mental state examination (MMSE) was performed as well as levels of amyloid beta‐40 (Aβ‐40) measured. PCI was calculated as difference between peak systolic and end diastolic flow velocity, divided by the flow velocity. Estrogen levels were measured in the plasma samples. The data were analyzed by unpaired two‐tailed t‐test and Pearson correlation with P values adjusted for false discovery rate.ResultsCKD patients had higher SBP, PP, PCI, LV systolic and diastolic volume (estimated by ECHO), lower LV ejection fraction, higher plasma NT‐proBNP and AST (CVD markers), glucose, triglycerides, plasma Aβ‐40 (Alzheimer’s disease marker), BUN and creatinine (CKD markers) and lower score in MMSE vs. healthy control (p<0.05). Plasma estrogen levels were significantly lower in CKD patients which correlated with the cognitive test scores and the renal function. Cognitive test results positively correlated with LV stroke volume, negatively correlated with PCI, a measurement of pulsatility of blood pressure, and negatively correlated with plasma ASP, a marker of CVD.ConclusionHigher PP, PCI, plasma Aβ‐40 and lower levels of estrogen and lower score in MMSE in female CKD patients supports our hypothesis that cardiovascular remodeling in women with CKD contributes to the development and progression of CI.